The aim of this research is to understand the nature of immune response defects to parasite antigens as an aid to the future rational design of parasite vaccines. We will investigate the nature of immune response gene defects in inbred mice using previously isolated cDNA clones of S.mansoni antigens. Subsequently, using human patients in family groups we will attempt to establish to what extent the observed variation in the human immune response has a genetic basis. The antibody responses to S.mansoni infection in mice are under genetic control. We have shown that the responses to particular antigens are regulated by genes in the MHC and elsewhere in the genome. Several possible mechanisms are proposed to account for this. Antigens will be produced in E.coli both as full length molecules and as partial deletion products and used as antigens and immunogens to identify possible regions of the antigen molecules responsible for suppression of the immune response. Hybrid antigens made by the fusion of two genes or subgenomic fragments will be used to test for suppression directed against particular parts of a polypeptide or to improve the immunogenicity of certain antigens. Using purified antigens we will determine whether the immune response gene effects are a consequence of infection or a property of the antigens themselves. Routes of antigen presentation will be varied to assess the role this plays in the immune response gene effects. Experimental immunizations with purified antigen during chronic infection will reveal induced suppressive effects should they exist. Panels of recombinant antigens and synthetic peptides will be used as antigens to fingerprint the immune responses of human patients in family studies to identify potential genetic influences on the human immune response. We will compare the antibody responses of infected mice with those induced by vaccination with irradiated cercariae and by immunization with recombinant and synthetic antigens. The responses will be compared both in terms of the epitopes recognized and the isotypes of antibody produced to each antigen. Further schistosome antigen clones relevant to immunity will be sought by a number of approaches. Suitable synthetic and recombinant antigens will be tested for their ability to induce immunity in experimental animals.